The impact of the number of electroconvulsive therapy sessions on relapse in major depressive disorder.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment of major depressive disorder (MDD). However, high relapse rates after ECT represent clinical problems. To date, influence of number of ECT sessions on relapse rate remains to be elucidated. We evaluated associations between number of ECT sessions and relapse rate. METHODS: This retrospective review collected clinical data of 53 patients with MDD who received ECT. They underwent a 1-year follow-up after their last ECT session. We performed survival analysis to evaluate associations between number of ECT sessions and time until rehospitalisation or suicide. RESULTS: The patients were divided into a higher number of ECT group (≧8 sessions) and lower number of ECT group (<8 sessions). No significant difference was found regarding the patients' clinical and demographic data. Survival analysis using log-rank test revealed that the cumulative survival rate in the higher number of ECT group (79%) was higher compared with the lower number of ECT group (49%) (p = 0.042). CONCLUSION: Patients who underwent a higher number of ECT had improved survival rate compared with those who received a lower number. Therefore, additional sessions might be necessary, even in patients who achieved remission within seven ECT sessions, to prevent relapse.Key pointsHigh rate of relapse after ECT is a key problem.Impact of the Number of ECT sessions on relapse remains to be elucidated.In the present study, the patients with MDD who underwent eight or more sessions of ECT showed significant lower relapse rate compared with those who received less than eight sessions.

Risperidone and 5-HT2A Receptor Antagonists Attenuate and Reverse Cocaine-Induced Hyperthermia in Rats.

BACKGROUND: Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action. METHODS: Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration. RESULTS: Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA. CONCLUSIONS: Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.

[Hospital Acquired Pneumonia in General Hospital Psychiatric Ward A Retrospective Study].

(Introduction) Pneumonia is a well-known major physical complication that can occur in the course of treatment for severe psychiatric disorders and antipsychotic treatment. However, there are few reports indicating the differences between pneumonia in the field of psychiatric medicine and the more commonly encountered type of pneumonia. In the present study, we examined the specific characteristics of in-hospital pneumonia in psychiatric wards and factors influencing the aggravation of this infection. (Methods) We retrospectively analyzed 22 patients in the psychiatric ward of Jichi Medi- cal University Hospital, which also has general wards, in whom pneumonia developed during hospitalization. We extracted occurrence, outcome, and sputum culture test results as charac- teristics. Severity of pneumonia was classified using the Pneumonia Severity Index (PSI) as follows : classes I -III, minor group (MG : 15 patients) and classes IV-V, moderate to severe group (MSG: seven patients). We examined the following factors related to the aggravation of pneumonia: body mass index (BMI), length of psychiatric treatment, number of hospital admis- sions, Global Assessment of Functioning (GAF) score, dose of antipsychotics, dose of benzodi- azepines (chlorpromazine and diazepam equivalent doses), and dose of antiparkinsonian agents (biperiden equivalent dose). (Results) Aspiration occurred prior to the onset of pneumonia in one patient, and one patient required ventilator management. There were no patient deaths. Streptococcus pneu- moniae and Staphylococcus aureus were detected in five and four patients, respectively. Nei- ther methicillin-resistant Staphylococcus aureus nor Pseudomonas aeruginosa was detected. In comparison with MG patients, MSG patients had significantly lower BMI (18.3 ?2.6 vs. 21.2? 3.5), significantly higher numbers of hospital admissions (3.4?i3.3 times vs. 1.1+?L1.4 times), and a significantly higher ratio of GAF scores of 30 or less (85.7% VS 33.3%). The doses of benzo- diazepines and antiparkinsonian agents were significantly higher for MSG patients in comparison with MG patients (benzodiazepines : 2.3?2.4 mg vs. 0.4?i1.1 mg; antiparkinsonian agents: 2.3?2.4 mg vs. 0.4? 1.1 mg). No significant differences were observed in the doses of antipsy- chotics. Sputum culture tests were performed in 18 patients. (Conclusion) Outcomes were comparatively favorable and the results of bacterial culture tests tended to show no antibiotic-resistant bacteria, differing in that regard from hospital- acquired pneumonia. In fact, the characteristics of cases of pneumonia in hospitalized psychiatric patients were similar to those of community-acquired pneumonia. Low BMI, multiple psychiatric ward admissions, and GAF scores of 30 or less all reflect poor mental control. The results of the present study suggest a relationship between the severity of pneumonia and both insufficient psychiatric treatment and the use of benzodiazepines and antiparkinsonian agents.

Differences in vulnerability to traumatic stress among patients with psychiatric disorders: One-year follow-up study after the Great East Japan Earthquake.

AIMS: The aim of this study was to evaluate differences in vulnerability to traumatic stress and the 1-year course of post-traumatic stress symptoms among patients with pre-existing psychiatric disorders after the Great East Japan Earthquake. METHODS: The Impact of Event Scale-Revised (IES-R) was used to assess post-traumatic stress symptoms in 612 patients with schizophrenic (ICD-10 F2; n = 163), mood (F3; n = 299), or neurotic disorders (F4; n = 150) at 1-4 months and again at 13-16 months after the disaster (retention rate: 68%). RESULTS: The mean IES-R total score for all diagnostic groups was 18.6 at index and 13.4 at follow up. The mean IES-R total score for patients with neurotic disorders (22.5) was significantly higher than that of patients with mood disorders (18.1) and schizophrenic disorders (15.9). At follow up, these scores decreased for all groups and inter-group differences were not observed. CONCLUSIONS: Vulnerability to traumatic stress after a disaster was most severe in patients with neurotic disorders, followed by mood disorders, and, lastly, schizophrenic disorders. This difference among the three diagnostic groups was not found 1 year after the disaster.

Risperidone suppresses caffeine-induced hyperthermia and hyperactivity in rats.

Caffeine, a methylxanthine alkaloid, works as a nonselective adenosine receptor antagonist. It is the most widely used psychostimulant drug worldwide. However, caffeine overdose can lead to acute intoxication, posing a clinical problem. Hyperthermia and hyperactivity are associated issues with acute caffeine intoxication; however, no definitive treatment exists. This study aimed to assess the ability of risperidone to attenuate caffeine-induced hyperthermia and hyperactivity while elucidating the unknown mechanisms of caffeine intoxication. The rats received intraperitoneal injections of saline, risperidone (0.25 mg/kg, 0.5 mg/kg), WAY-100635, ketanserin, haloperidol, sulpiride, or SCH 23390, 5 min after the administration of caffeine (25 mg/kg). Subcutaneous temperature and activity counts were measured using nano tag ® for up to 90 min. In vivo microdialysis was used to determine the effect of risperidone on caffeine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline (NA) concentrations in the anterior hypothalamus. Rats were injected with caffeine (25 mg/kg), followed by saline or risperidone (0.5 mg/kg) 5 min later. The levels of DA, 5-HT, and noradrenaline were measured every 15 min for up to 90 min after caffeine administration. Risperidone and 5-HT2A receptor antagonist ketanserin attenuated caffeine-induced hyperthermia and hyperactivity. Haloperidol and dopamine D1 antagonist SCH-23390 exacerbated hyperthermia without any effect on the hyperactivity. In the microdialysis study, risperidone treatment further attenuated caffeine-induced 5-HT elevation, but not DA and NA. Our results indicate that risperidone attenuates caffeine-induced hyperthermia and hyperactivity by blocking 5-HT2A receptor activity and may be potentially useful for treating caffeine intoxication.

[Effects of psychological distress due to the Great East Japan Earthquake, tsunami, Fukushima Nuclear Power Plant disasters on psychiatric symptoms in patients with mental disorders: observational studies in Tochigi].

BACKGROUND: The Great East Japan Earthquake and subsequent tsunami of March 11, 2011 severely damaged a widespread region of northeastern Japan. Consequently, the Fukushima Nuclear Power Plant experienced a level seven 3 reactors melted down, which released a large amount of radioactive materials into the air. Due to the structural damage and radiation leaks, the victims are facing prolonged psychological distress. METHODS: Eighty-two subjects with mental disorders who made their initial visit during the first 4 months after the earthquake and one hundred and ninety-four subjects with mental disorders who had been admitted during the first one year after the earthquake to the Jichi Medical University Hospital, which is located at the edge of the disaster-stricken region, were recruited for this study. Enrolled participants were assessed according to ICD-10. A questionnaire survey was employed to evaluate the severity of psychological distress and total amount of damage. RESULTS: The conditions of 22% of the outpatients had been worsened by the psychological distress related to the earthquake. Seven percent of the patients who had been hospitalized showed marked exacerbations due to the psychological distress associated with the disaster. COMMENTS: It is of note that the exacerbation of psychiatric symptoms due to the disaster was evident among patients with mental disorders who lived even at the edge of the disaster area (i. e., subject to an earthquake intensity of 5 upper and 150 km from the Fukushima Nuclear Power Plant). The results suggest that the close follow-up of disaster victims with mental disorders is of critical importance.

An Inpatient Observational Study: Characteristics And Outcomes Of Avoidant/Restrictive Food Intake Disorder (ARFID) In Children And Adolescents In Japan.

PURPOSE: To determine the clinical characteristics and course of severe avoidant/restrictive food intake disorder (ARFID) in hospitalized children and adolescents and compare them with those of patients with restricting-type anorexia nervosa (R-AN). PATIENTS AND METHODS: We conducted a retrospective chart review of inpatients diagnosed with ARFID or R-AN based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, at Jichi Children's Medical Center Tochigi between April 1, 2007 and March 31, 2017. We compared the characteristics of the ARFID and R-AN patients at admission, during hospitalization, and after discharge. RESULTS: Both the ARFID (n=13) and R-AN (n=79) patients required hospitalization for their medically unstable state. The features of ARFID group included concern about the aversive consequences of eating and avoidance of eating due to sensory concerns. Significant differences were found at admission between ARFID and R-AN groups in age (10.7 vs 12.7 years), family history of mental disorders (46.2% vs 17.7%), comorbid developmental disorders (6 vs 3 cases), and the time from onset to admission (3.9 vs 6.3 months). The body weight status, % ideal body weight (%IBW), % expected body weight (%EBW), <75% IBW rate, and <75% EBW rate did not differ significantly between the two groups at admission or discharge. The duration of post-discharge outpatient follow-up treatment did not differ significantly between ARFID and R-AN groups (15.3 vs 18.4 months); however, ARFID group recovery rate was significantly higher than that of R-AN group (77% vs 43%). The reasons that the patients with ARFID had significantly better outcomes than the R-AN patients remain unclear. Compared to those in previous studies, the present patients were younger and demonstrated better outcomes. Our results indicate that the body weight status is similar between ARFID and R-AN patients, but the ARFID patients achieved better outcomes. CONCLUSION: These findings suggest that early onset in childhood, early disease recognition, and early intervention are important factors for achieving better outcomes for patients with ARFID.

Oseltamivir (Tamiflu) increases dopamine levels in the rat medial prefrontal cortex.

Oseltamivir (Tamiflu), a neuraminidase inhibitor, is effective for treating both seasonal flu and H5N1 influenza A virus infection. Oseltamivir is generally well tolerated, and its most common adverse effects are nausea and vomiting. However, neuropsychiatric behaviors including jumping and falling from balconies by young patients being treated by oseltamivir have been reported from Japan; this has led to warnings against its prescribing by many authorities. The pharmacological mechanism of the neuropsychiatric effects of oseltamivir remains unclear. Many studies reported that changes in neurotransmission and abnormal behaviors are closely related. We investigated the changes in dopamine and serotonin metabolism after systemic administration of oseltamivir in the medial prefrontal cortex (mPFC) of rats by using microdialysis. After systemic administration of oseltamivir (25mg/kg or 100mg/kg; intraperitoneally (i.p.)), extracellular dopamine in the mPFC was significantly increased as compared to the control values; 3,4-dihydroxyphenylacetic acid and homovanillic acid, the metabolites of dopamine, had also increased significantly. Serotonin was unchanged after the administration of oseltamivir. These findings suggest that oseltamivir increased dopamine release in the mPFC; further, they suggest that the increase in dopamine during oseltamivir treatment may have caused abnormal behaviors in young patients. In cases where oseltamivir is prescribed to children, close observation is required.

Risperidone attenuates and reverses hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug. Despite an increase in the number of fatalities related to its use, no definite therapeutic method has been established thus far. In the present study, risperidone's ability to attenuate MDMA-induced hyperthermia and its mechanism of action were investigated in rats. The pharmacological effect of MDMA was evaluated using microdialysis. In the body temperature experiment, administration of risperidone before and after MDMA administration significantly suppressed MDMA-induced hyperthermia in a dose-dependent fashion. Furthermore, risperidone completely inhibited MDMA-induced hyperthermia at a low ambient temperature. Moreover, pretreatment with ritanserin, ketanserin, or R-96544, all of which are 5-HT(2A)-receptor antagonists, significantly prevented MDMA-induced hyperthermia. On the other hand, pretreatment with WAY-100635 (a 5-HT(1A) receptor antagonist), SB 206553 (a 5-HT(2B/2C) receptor antagonist), or SB 242084 (a 5-HT(2C) receptor antagonist) did not prevent MDMA-induced hyperthermia. Pretreatment with haloperidol, which blocks the dopamine (DA) receptors D(2) and D(1), significantly prevented MDMA-induced hyperthermia. However, sulpiride and L-741626, which are D(2) receptor blockers, did not prevent MDMA-induced hyperthermia. Pretreatment with SCH 23390 (a D(1) receptor antagonist) significantly prevented MDMA-induced hyperthermia. Furthermore, postadministration of ritanserin, haloperidol, and SCH23390 reversed MDMA-induced hyperthermia. These results demonstrate that the mechanism underlying the suppression of MDMA-induced hyperthermia by risperidone is primarily based on the drug's potent 5-HT(2A) receptor blocking effect, and to a lesser extent, on its D(1) receptor blocking effect. A microdialysis study showed that when MDMA (10mg/kg) was subcutaneously (s.c.) injected into the rats, the DA and serotonin (5-HT) levels in the anterior hypothalamus of the rats increased approximately 10- and 50-fold, respectively, as compared to their preadministration levels. These increases in the DA and 5-HT levels after MDMA injection were significantly suppressed by pretreatment with risperidone (0.5mg/kg). This suggested that both the DA and 5-HT systems were involved in the induction of hyperthermia by MDMA. Taken together, the present study's results indicate that risperidone may be an effective drug for the treatment of MDMA-induced hyperthermia in humans.

Neuroleptic malignant syndrome and serotonin syndrome.

This chapter is focused on drug-induced hyperthermia with special regard to use of antipsychotics and antidepressants for the treatment of schizophrenia and major depression, respectively. Neuroleptic malignant syndrome (NMS) develops during the use of neuroleptics, whereas serotonin syndrome is caused mainly by serotoninergic antidepressants. Although both syndromes show various symptoms, hyperthermia is the main clinical manifestation. In this review we describe the historical background, clinical manifestations, diagnosis, and differential diagnosis of these two syndromes based on our observations on the experimental and clinical data.

Behavioral stress and activated serotonergic neurotransmission induce XBP-1 splicing in the rat brain.

The splicing of 26 nucleotides in the coding region of the X-box binding protein-1 (XBP-1) transcript to generate a mature active transcription factor is a part of the unfolded protein response to intracellular endoplasmic reticulum stress. In this study, we demonstrated that XBP-1 splicing is promptly induced in the rat brain including the hippocampus by both inescapable electric foot shock (IS) and pharmacologically manipulated activation of 5-hydroxytryptamine release in a dose-dependent manner. By administering ketanserin, a 5-hydroxytryptamine 2A antagonist, however, we could only partially block the increased splicing by IS and observed that the splicing was not influenced by lithium carbonate pretreatment. Although it is still unclear whether the enhanced unfolded protein response functions neuroprotectively by modulating the rate of general translation and increasing chaperone proteins or whether it eventually induces cellular damage by triggering apoptosis, the present results indicate the possible existence of a new adaptive intracellular signaling pathway in the brain that responds to environmentally challenged behavioral stress loading.

Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome.

The serotonin (5-HT) syndrome is the most serious toxic interaction of antidepressants, but no pharmacotherapy has yet been established. In the present study, we created an animal model of the 5-HT syndrome by intraperitoneally injecting rats with clorgyline (2 mg/kg) and 5-hydroxy-L-tryptophan (5-HTP) (100 mg/kg) and evaluated the effectiveness of potent 5-HT(2A) receptor antagonists and GABA-enhancing drugs, including diazepam and chlormethiazole. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured by microdialysis. In the group pre-treated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min after administration. Pre-treatment with potent 5-HT(2A) receptor antagonists prevented the development of hyperthermia and death in the rats. Pre-treatment with diazepam, 10 and 20mg/kg, and chlormethiazole, 50 and 100mg/kg, attenuated the development of hyperthermia. Although neither of these drugs completely prevented the rats from dying, they prolonged their survival time. Regardless of the type of therapeutic agents, the concentration of 5-HT increased to about 1100-fold the pre-administration level. The NA levels in the saline group increased to about 16-fold the pre-administration levels, but the increase was significantly lower in the rats that survived as a result of drug therapy. These results suggest that GABA-mimetic drugs may be effective against the 5-HT syndrome, although they have a somewhat weaker effect than the potent 5-HT(2A) receptor blockers, and that not only is 5-HT activity increased in the brain in the 5-HT syndrome, but the NA system is also enhanced.

Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex.

Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT1A receptor agonism as well as 5-HT2A and D2 receptor antagonism. We investigated the effect of perospirone in combination with fluoxetine on dopamine release in the rat medial prefrontal cortex using microdialysis. Perospirone and fluoxetine increased dopamine release to 270 and 210% of the baseline value, respectively. A combination of perospirone and fluoxetine markedly increased dopamine release to 800% of the baseline value. Pretreatment with a selective 5-HT1A receptor antagonist, WAY 100635, suppressed the increase in dopamine levels induced by the administration of perospirone and fluoxetine to 330% of the baseline value. These findings suggest that perospirone potentiates fluoxetine-induced dopamine increases in part via the action of the 5-HT1A receptor and may augment the effect of fluoxetine in treatment-resistant depression.

Extracellular serotonin, dopamine and glutamate levels are elevated in the hypothalamus in a serotonin syndrome animal model induced by tranylcypromine and fluoxetine.

Serotonin (5-HT) syndrome is a potentially fatal condition associated with various combinations of serotonergic drugs. The present study was undertaken to demonstrate that nervous systems other than the 5-HT system also participate in the pathophysiology of 5-HT syndrome. Concentrations of 5-HT, dopamine (DA) and glutamate in the hypothalamus were measured in two different 5-HT syndrome animal models using a microdialysis technique. The first model was induced by tranylcypromine, a nonselective monoamine oxidase (MAO) inhibitor (3.5 mg/kg) and fluoxetine, a selective serotonin reuptake inhibitor (SSRI) (10 mg/kg). The second model was induced by clorgyline, an MAO-A inhibitor (1.2 mg/kg) and 5-hydroxy-L-tryptophan, a precursor of 5-HT (5-HTP) (80 mg/kg). In the first model, the levels of 5-HT and DA increased by 40-fold and 44-fold, respectively, compared with the preadministration levels. In the second model, the concentrations of 5-HT increased by up to 140-fold, whereas DA levels increased by only 10-fold, of the preadministration levels. Although the level of glutamate in the second model barely changed, a delayed increase in the glutamate level was observed in the first model. These findings suggest that not only hyperactivity of the 5-HT system, but also hyperactivity of the DA system, are present in 5-HT syndrome, and that the glutamatergic system is influenced in some 5-HT syndrome cases in which the DA concentration markedly increases.

Anger with murderous impulse induced by lamotrigine.

OBJECTIVE: To report two cases of major depressive disorder in which lamotrigine (LTG) induced anger with murderous impulse. PATIENTS: Case 1 was a 22-year-old man with symptoms of obsessive-compulsive disorder who developed major depressive disorder with antidepressant-induced hypomanic episodes. Case 2 was a 23-year-old woman experiencing an antidepressant-refractory depressive episode for whom remission was achieved by switching to a mood stabilizer and antipsychotics. In both cases LTG was started to treat the depressive episode. RESULTS: Case 1 manifested with anger and murderous impulse when taking 125 mg/day of LTG. A reduction to 75 mg/day calmed this anger. Case 2 manifested with the same symptom when taking 25 mg/day of LTG, and the symptom immediately disappeared upon stopping LTG. CONCLUSIONS: Use of LTG for epilepsy in intellectually disabled patients was reported to be associated with onset or exacerbation of aggressive or violent behavior. The two cases would suggest that LTG may cause anger so severe as to be accompanied with murderous impulse when administered to patients with mood disorders. Physicians should be cognizant of this possible, albeit infrequent, adverse effect even in use of LTG for mood disorders.

Second case report of successful electroconvulsive therapy for a patient with schizophrenia and severe hemophilia A.

Electroconvulsive therapy (ECT) is used for medication-resistant and life-threatening mental disorders, and therefore it occupies an important position in psychiatric treatment. ECT reportedly increases intracranial pressure and is suspected of increasing the risk of intracranial hemorrhage, especially in patients with hemorrhagic diseases such as hemophilia. A decrease in or loss of blood coagulation factors, including factor VIII and factor IX, are found in hemophilia A and B, respectively. Psychiatrists may hesitate to perform ECT on patients with bleeding tendencies, such as in hemophilia. Here, we report the successful use of ECT on a neuroleptic-resistant patient with schizophrenia and severe hemophilia A. We performed ECT 16 times supplemented with coagulation factor VIII to prevent intracranial and systematic hemorrhage. We administered factor VIII concentrates to the patient to keep factor VIII activity at 30%-40% during ECT. The patient did not show bleeding or other complications during the ECT sessions. We suggest that pretreatment with factor VIII can help manage the increased risks of intracranial and systematic bleeding during ECT that is present in patients with hemophilia A. The present report supports the idea of performing ECT safely on patients with hemophilia A by administering factor VIII.